Project Summary/Abstract In the United States, Primary Open Angle Glaucoma (POAG) is the second leading cause of blindness in the general population and the leading cause of blindness among African Americans. Due to the asymptomatic nature of the disease even at considerably advanced stages, many patients are not diagnosed with POAG until irreversible blindness has occurred. Fundamental questions about basic pathogenic mechanisms of POAG remain unanswered. Improved treatment for glaucoma patients requires better understanding of the disease mechanisms and development of early detection strategies. Our broad long term goals are to understand the disease pathophysiology and to provide tools for early detection and better treatment of this devastating disease. A genetic component for POAG is suggested by the fact that family history of the disease is one of the most important risk factors. Identification of genes contributing to POAG is of primary importance to develop improved treatment and early diagnosis strategies for POAG. Over 4 decades ago, a colony of Beagles with hereditary POAG was established, and to this day remains the only naturally occurring animal model for human POAG. Taking advantage of this well-established model, we have recently identified a small genetic interval that contains the genetic mutation causing POAG in the Beagles. The objective of this project is to identify the genetic mutation causing POAG in Beagles. To accomplish this goal, we will apply the emergent technology of Next Generation Sequencing to determine the DNA sequence of the entire region. Candidate genetic variants will be identified by comparing the sequences of affected and unaffected dogs from the POAG Beagle colony and unrelated unaffected Beagles. These genetic variants will identify candidate disease genes. Validity of the candidate genes will be tested by investigating their expression in ocular tissues from affected and unaffected Beagles. The work proposed here would promote and extend the use of the new genetic technologies of sequence capture and Next Generation Sequencing in the application of disease gene identification. Successful completion of this project would result in identification and verification of a gene causing POAG, which will likely be a major contribution to glaucoma research leading to improved treatment and early detection for glaucoma patients. PUBLIC HEALTH RELEVANCE: Narrative The main objective of this proposal is to identify the gene causing primary open angle glaucoma in Beagles. Based on our preliminary results, we project that the gene will be novel and involved in aqueous humor outflow regulation.